Antidepressant-like action of agmatine in the acute and sub-acute mouse models of depression: a receptor mechanism study

Abstract

Previous studies have shown that agmatine, a potential neuromodulator or co-transmitter, exhibited antidepressant-like action in animal models, yet its mechanism, especially the receptor mechanism, remains unclear. In the present study, using efaroxan, a preferential antagonist of I imidazoline receptor (IR) and yohimbine, an antagonist of α adrenergic receptor (αAR), we investigated the roles of IR and αAR in agmatine's antidepressant-like effect in acute and sub-acute depression models in mice. We found that in the tail-suspension test (TST) and the forced swimming test (FST), acute administration of agmatine (20 and 40 mg/kg, p.o.) significantly shortened the immobility time. Concurrent administration of efaroxan (1 mg/kg, i.p.) completely abolished the antidepressant-like effects of agmatine (40 mg/kg, p.o.) whereas yohimbine (5 mg/kg, i.p.) failed to exert similar effects, suggesting that the acute antidepressant-like effects of agmatine was mainly mediated by IR but not αAR. Additionally, in the learned helplessness (LH) test, repeated administration of agmatine (20 mg/kg, p.o., q.d.) for 5 days significantly decreased the escape latency and the number of escape failure, and these effects were respectively abolished by concurrent administration of efaroxan (0.5 mg/kg,i.p., q.d.) and yohimbine (3 mg/kg, i.p., q.d.) for 5 days, suggesting that the antidepressant-like action of agmatine in the LH test was achieved via the activation of both IR and αAR. In summary, we found that the antidepressant-like effects of agmatine in the TST and the FST were mediated by activating IR and in the sub-acute LH test were mediated by activating both IR and αAR.

Agmatine modulates spontaneous activity in neurons of the rat medial habenular complex—a relevant mechanism in the pathophysiology and treatment of depression?

“… 24 ). In support of our data, the involvement of I1 imidazoline receptors with the antidepressant-like action of agmatine in mouse models of depression has been elegantly demonstrated using different behavioral tests 82 . Interestingly, the mouse I1 receptor homolog IRAS/nischarin was found to be downregulated in the prefrontal cortex of postmortem brains from individuals with major depression who received antidepressant drug treatment 83 .…”

Effects of imidazoline agents in a rat conditioned place preference model of addiction

“…Both IDZ and EFR blocked the antidepressant effect induced by AG (Kotagale et al 2020a ). EFR confirmed the involvement of imidazoline receptors in the antidepressant effect of AG in models of acute and subacute depression in mice (Chen et al 2018 ), in carbophenyline analgesia in neuropathic pain caused by oxaliplatin in mice (Micheli et al 2020 ), in maintaining the respiratory drive in newborn rats (Sato et al 2017 ) and in the cardioprotective effect exerted by dexmedetomidine against ischemia/reperfusion injury in the spontaneously hypertensive rats (Yoshikawa et al 2018 ). EFR stimulated insulin secretion in the MIN6 cell line (Lin et al 2017 ), and IDZ reduced hepatic fibrosis in mice (Xuanfei et al 2017 ).…”

“…It decreased neuroinflammation and promoted neuroplasticity (Kotagale et al 2020b ). AG exerted antidepressant effects alone (Gawali et al 2017 ; Chen et al 2018 ; Ostadhadi et al 2018 ; Neis et al 2018 ) or in combination with other drugs like muscimol, diazepam (Neis et al 2020 ), or ketamine (Neis et al 2018 ). It also has anti-inflammatory (Neis et al 2017 ), anxiolytic (Gawali et al 2017 ), and anticonvulsant (Bahremand et al 2018 ) properties.…”

“…The 2-(2,3-dihydro-1,4-benzodioxin-3-yl)-4,5-dihydro-1 H -imidazole compound, known as IDZ, and the 2-(2-ethyl-3 H -1-benzofuran-2-yl)-4,5-dihydro-1 H -imidazole compound, known as EFR, act as an antagonist on -adrenergic receptors and as an antagonist on imidazoline receptors, for the former and for the latter (Bousquet et al 2020 ). Some recent studies have demonstrated the variety of the effects these compounds possess and the involvement of the imidazoline receptor system (Sato et al 2017 ; Xuanfei et al 2017 ; Chen et al 2018 ; Kotagale et al 2020b ;). Both compounds blocked the antidepressant effect of statins and the synergism produced by the coadministration of statins and AG (Rahangdale et al 2021 ).…”

Peculiarities of Motor Activity of Rats in Simulation Pharmacological Depressogenic States

“…The Porsolt test, "Tail Suspension Test", Forced Swim Test are used for screening study of potential antidepressants [6,7]. The Porsolt test determines the following indicators: the latency period of the first "hanging" and the total immobility time (sec.…”